WO2005075488A1 - Procede de fabrication de fosphenytoine, sel de sodium - Google Patents

Procede de fabrication de fosphenytoine, sel de sodium Download PDF

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Publication number
WO2005075488A1
WO2005075488A1 PCT/CH2004/000063 CH2004000063W WO2005075488A1 WO 2005075488 A1 WO2005075488 A1 WO 2005075488A1 CH 2004000063 W CH2004000063 W CH 2004000063W WO 2005075488 A1 WO2005075488 A1 WO 2005075488A1
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WO
WIPO (PCT)
Prior art keywords
diphenyl
phosphite
methyl
ester
phosphonooxy
Prior art date
Application number
PCT/CH2004/000063
Other languages
German (de)
English (en)
Inventor
Hartmut Zinser
Guisep Derungs
Original Assignee
Cilag Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cilag Ag filed Critical Cilag Ag
Priority to PCT/CH2004/000063 priority Critical patent/WO2005075488A1/fr
Priority to US10/587,189 priority patent/US20070219378A1/en
Publication of WO2005075488A1 publication Critical patent/WO2005075488A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • Sodium fosphenytoin is the short name for the 5,5-diphenyl-3- [(phosphonooxy) methyl] -2, 4-imidazolidinedione disodium salt, which is used as an anticonvulsant, antiepileptic and antiarrhythmic agent.
  • Preparations containing sodium fosphenytoin are sold under the name Cerebyx.
  • sodium fosphenytoin is prepared by adding hydroxymethylphenytoin, i.e. 3- (hydroxymethyl) -5, 5-diphenyl-2, 4-imidazolinedione, converted into 3-chloromethyl-phenytoin, reacted with silver dibenzylphosphonate, cleaved the two benzyl groups in the diester obtained by catalytic hydrogenation and finally using sodium hydroxide solution the desired di -Sodium salt forms.
  • diesters of the type mentioned can be prepared without the need to use a silver salt by reacting 3-chloro- or bromomethyl-phenytoin with an alkali metal phosphonate, such as potassium or sodium dibenzyl phosphonate.
  • an alkali metal phosphonate such as potassium or sodium dibenzyl phosphonate.
  • sodium phosphenytoin can be prepared advantageously by adding 3- (hydroxymethyl) -5, 5-diphenyl-2, 4-imidazolinedione with a di- or triester of phosphorous acid activated by an oxidizing agent, the ester groups of which can be split off selectively from the reaction product, reacted, split off the ester groups from the phosphoric acid diester-2, 5-dioxo-4, 4-diphenyl-imidazolidin-1-ylmethyl ester obtained and the 5, 5-diphenyl-3- obtained [(phosphonooxy) methyl] -2, 4-imidazolidinedione converted into its disodium salt.
  • a halogenating agent such as elemental bromine, N-bromosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin, tetrabromomethane, trichlorobromomethane, elemental chlorine, N-chlorosuccinimide, trichloroisocyanuric acid and hexachloroacetone acid, is expediently used as the oxidizing agent for activating the phosphorous acid ester the like, with elemental bromine being preferred.
  • Such halogenation is conveniently carried out in the presence of a base, for example in the presence of pyridine, 2,6-lutidine, 2, 4, 6-collidine, triethylamine and the like.
  • a polar aprotic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolione, 1, 3-dimethyl-2-imidazolidinone and the like, is expediently used as the solvent.
  • phosphite esters 0.5-5.0 equivalents, preferably 1.1-1.4 equivalents, of phosphite esters, 0.5-10.0 equivalents, preferably 1.5-3.0 equivalents of oxidizing agents and 0.5-10.0 equivalents, preferably 1.5-3.0 equivalents of base, based on the hydroxymethylphenytoin.
  • ester groups which can be cleaved selectively from the reaction product are, in particular, those whose cleavage under mild acidic conditions (e.g. tert-butyl or 2,2,2-trichloroethyl) is oxidative (e.g. silylated
  • Alkyl groups can be removed under mild basic conditions (e.g. ethyl) or photochemically (e.g. nitrobenzyl), but especially hydrogenolytically removable groups such as the benzyl group and substituted benzyl groups such as 4-methoxybenzyl, 4-bromobenzyl, 2-methoxybenzyl, 2,4 -
  • esters of phosphorous acid their ester groups are selective from the reaction product can be split off, in particular di-tert-butyl phosphite, dibenzyl phosphite, bis-4-methoxybenzyl phosphite, bis-4-bromobenzyl phosphite, bis-4-nitrobenzyl phosphite, bis- (2,4-dimethoxybenzyl) phosphite, bis-2 , 2, 2-trichloroethyl phosphite, bis (2-trimethylsilylethyl) phosphite, triallyl phosphite or tribenzyl phosphite and also dimethyl phosphite, diethyl phosphite, trimethyl phosphite or triethyl phosphite.
  • esters of phosphorous acid used in the process according to the invention are known or easily accessible by any process familiar to a person skilled in the art.
  • the cleavage of the ester groups from the 2, 5-dioxo-4, 4-diphenylimidazolidin-1-ylmethyl ester of phosphoric acid, in particular by hydrogenation, is conveniently carried out in a mixture of water and a water-miscible solvent, for example in methanol / water , Isopropanol / water, acetone / water, 2-butanone / water and the like; preferably a buffer is added, for example acetic acid / acetate.
  • 3- (hydroxymethyl) -5, 5-diphenyl-2,4-imidazolinedione is replaced by elemental bromine or N-
  • the activation of the dibenzyl phosphite by means of elemental bromine or N-bromosuccinimide and the reaction of the activation product with the 3- (hydroxymethyl) -5, 5-diphenyl -2, 4 -imidazolinedione and on the other hand the hydrogenation of the phosphoric acid dibenzyl ester-2, 5-dioxo-4, 4-diphenyl-imidazolidin-1-ylmethyl ester and the conversion of the 5,5-diphenyl-3- [(phosphonooxy) methyl] -2, 4-imidazolidinedione into its disodium salt in carried out one work step each.
  • the temperature for the various operations of the method according to the invention is expediently in the range from approximately -30 ° C. to approximately + 80 ° C., preferably in the range from approximately -10 ° C. to approximately + 30 ° C.
  • the process according to the invention does not use a phosphate (phosphorus in the + V oxidation state), but rather a phosphite (phosphorus in the + III oxidation state).
  • This phosphite is activated in situ with an oxidizing agent, preferably a halogenating agent, and then reacted directly with the hydroxymethylphenytoin known from the literature and readily available from commercially available phenytoin.
  • a phosphoric acid diesester-2 is prepared in a single operation in order to prepare 5, 5-diphenyl-3- [(phosphonooxy) methyl] -2, 4-imidazolidinedione disodium salt , 5-dioxo-4, 4-diphenyl-imidazolidin-l-ylmethyl ester, whose phosphoric diester structural element can be cleaved selectively, in 5, 5-diphenyl-3- [(phosphonooxy) methyl] -2, 4-imidazolidinedione and this in transferred its disodium salt; this aspect is an essential part of the present invention, also taken on its own.
  • the orange suspension obtained was mixed with 250 g of water and 50 g of 36% sodium thiosulfate solution (about 2 mmol / g), whereupon discoloration was observed rapidly. After adding 650 ml of ethyl acetate, the phases were separated and the organic phase was washed with 50 g of saturated sodium carbonate solution. The organic phase was concentrated and the yellow-orange oil obtained was taken up in a mixture of 350 ml of acetonitrile and 350 ml of water. After inoculation, a voluminous precipitate precipitated out, which was filtered off and dried in vacuo; Yield 200 g (68%).
  • the orange suspension obtained was mixed with 20 g of water and 1 g of 36% sodium thiosulfate solution, whereupon decolorization was observed rapidly. After adding 50 ml of ethyl acetate, the phases were separated and the organic phase was saturated twice with 20 ml each

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)

Abstract

Le fosphénytoïne, 5,5-diphényl-3-[(phosphonooxy) méthyl]-2,4-imidazolidindion-sel disodique, qui est un agent anticonvulsif, antiépileptique et antiarrhythmique connu, peut être fabriqué en faisant réagir le 3-(hydroxyméthyl)-5,5-diphényl-2, 4-imidazolindion, au moyen d'un di- ou d'un triester de l'acide phosphoreux, activé par un oxydant, dont les groupes ester sont dissociables sélectivement du produit de la réaction, en séparant les groupes ester du diester-2,5-dioxo-4,4-diphényl-imidazolidine-1-ylméthylester d'acide phosphorique obtenu, et en transformant le 5,5-diphényl-3-[(phosphonooxy)méthyl)]-2,4-imidazolidindion obtenu en son sel disodique. L'oxydant est avantageusement un agent d'halogénation, tel que le brome élémentaire ou le N-bromosuccinimide et, comme ester de l'acide phosphoreux, on utilise avantageusement le dibenzylphosphite. Ce qui est d'une importance particulière est le fait, considéré en lui-même, qu'on peut transformer en une seule étape, un 2,5-dioxo-4,4-diphényl-imidazolidine-1-ylméthylester de l'acide phosphorique, dont l'élément de structure diester de l'acide phosphorique peut être dissocié sélectivement, en 5,5-diphényl-3-[(phosphonooxy)méthyl]-2,4-imidazolidindion, et celui-ci en son sel disodique.
PCT/CH2004/000063 2004-02-05 2004-02-05 Procede de fabrication de fosphenytoine, sel de sodium WO2005075488A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CH2004/000063 WO2005075488A1 (fr) 2004-02-05 2004-02-05 Procede de fabrication de fosphenytoine, sel de sodium
US10/587,189 US20070219378A1 (en) 2004-02-05 2004-02-05 Method for Producing Sodium Fosphenytoin

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CH2004/000063 WO2005075488A1 (fr) 2004-02-05 2004-02-05 Procede de fabrication de fosphenytoine, sel de sodium

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WO (1) WO2005075488A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007014326A1 (fr) * 2005-07-27 2007-02-01 University Of Southern California Acides amines a base de coumarine pouvant etre utilises dans des analyses d'activite enzymatique et de specificite de substrat
WO2007022568A1 (fr) * 2005-08-25 2007-03-01 Steven Michael Weiss Réduction d’un dommage myocardique et de l’incidence d’une arythmie survenant à la suite d’une perte, d’une réduction ou d’une interruption de la circulation coronarienne

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279279B (zh) * 2016-08-15 2018-06-01 广安凯特制药有限公司 一种磷苯妥英钠的制备工艺

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997041132A1 (fr) * 1996-04-30 1997-11-06 Warner-Lambert Company Procede perfectionne pour la synthese de diesters de l'ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethylique de l'acide phosphorique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH696765A5 (de) * 2004-06-02 2007-11-30 Cilag Ltd Verfahren zur Herstellung von Natrium-fosphenytoin.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997041132A1 (fr) * 1996-04-30 1997-11-06 Warner-Lambert Company Procede perfectionne pour la synthese de diesters de l'ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethylique de l'acide phosphorique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
OZA V B ET AL: "A MILD PREPARATION OF PROTECTED PHOSPHATE ESTERS FROM ALCOHOLS", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 60, no. 12, 16 June 1995 (1995-06-16), pages 3680 - 3684, XP000509383, ISSN: 0022-3263 *
VARIA S A ET AL: "PHENYTOIN PRODRUGS III: WATER-SOLUBLE PRODRUGS FOR ORAL AND/OR PARENTERAL USE", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION. WASHINGTON, US, vol. 73, no. 8, 1 August 1984 (1984-08-01), pages 1068 - 1073, XP000604620, ISSN: 0022-3549 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007014326A1 (fr) * 2005-07-27 2007-02-01 University Of Southern California Acides amines a base de coumarine pouvant etre utilises dans des analyses d'activite enzymatique et de specificite de substrat
US9045507B2 (en) 2005-07-27 2015-06-02 University Of Southern California Coumarin-based amino acids for use in enzyme activity and substrate specificity assays
WO2007022568A1 (fr) * 2005-08-25 2007-03-01 Steven Michael Weiss Réduction d’un dommage myocardique et de l’incidence d’une arythmie survenant à la suite d’une perte, d’une réduction ou d’une interruption de la circulation coronarienne
US9629817B2 (en) 2005-08-25 2017-04-25 Steven Michael Weiss Reducing myocardial damage and the incidence of arrhythmia arising from loss, reduction or interruption in coronary blood flow

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